JP2006124296A - Medicinal composition for treatment of helicobacter pylori infectious disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicinal composition for the treatment of Helicobacter pylori infectious diseases having low side action. <P>SOLUTION: An extract of Santali lignum and a sesquiterpene alcohol separated from the extract have anti-pylori bacteria activity and are promising as an anti-pylori agent wanted from clinical field. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical composition comprising an sandalwood-containing component as an active ingredient and having an antibacterial action, particularly a high antibacterial action against Helicobacter pylori (hereinafter referred to as H. pylori) bacteria. The present invention further relates to a pharmaceutical composition having sesquiterpene alcohol, which is a sandalwood-containing component, as an active ingredient and having high antibacterial activity against H. pylori.

  In Japan, infection of H. pylori has been confirmed at a high rate mainly in middle-aged and elderly people. The infection rate in the second and thirties is 20-40%, and in the age of 50 and over, it increases with age, 70-80% . It is considered as one of the onset and recurrence factors of gastritis, gastrointestinal ulcer, gastric cancer, etc. It is said that this bacterium is present in more than 95% of Japanese early gastric cancer. The rate of gastric cancer by the age of 75 varies by a factor of 6 with or without H. pylori, and eradication reduces the risk of gastric cancer to an average of 1/3 or less. Currently, triple therapy using amoxicillin (AMPC), clarithromycin (CAM) and lansoprazole (LPZ) is recommended for sterilization. Three-drug combination therapy is effective against many H. pylori infections, but side effects caused by eradication and the emergence of drug-resistant H. pylori have been reported.

  Sandalwood is a plant of the Santalaceae family that is distributed mainly in India, Indonesia, Malaysia, and China. It is used as a stomach stomach and an analgesic, and is now generally used as a raw material for producing sandalwood oil for musk. . Sandalwood contains 1.6-6.0% essential oil, the main component of which is α / β-santalol (about 90%). However, there are no reports that sandalwood or α / β-santalol has anti-pylori activity.

  In particular, CAM-resistant H. pylori has increased in recent years and is a factor that significantly reduces the sterilization rate. For these reasons, the development of antibacterial agents that exhibit clinically sufficient H. pylori eradication effects at smaller doses and have fewer side effects and excellent properties as pharmaceutical preparations is eagerly desired.

  The inventors of the present invention have found that sandalwood extract and sesquiterpene alcohols isolated from the extract have anti-pylori activity and are promising as clinically awaited anti-pylori agents. The present invention has been completed based on such findings.

The anti-pylori activity of sandalwood extract and components isolated from the extract is shown by the following test examples.
Test example 1
Screening for antibacterial activity against H. pylori was performed by the disk diffusion method. As a test bacterium, H. pylori standard strain ATCC43504 and clinical isolate SS-1 were used. Helicobacter pylori is Brucella broth containing 5% horse serum and cultured at 37 ° C for 4 days in a microaerobic environment (Anaeropak Helico, Mitsubishi Gas Chemical). Final concentration of 1 x 10 ⁷ to 1 x 10 ⁸ CFU (colony) Foaming unit) / mL was diluted with sterile physiological saline. This bacterial solution was uniformly smeared on a ISO SENSI TEST agar plate containing 10% by volume equine defibrinated blood using a sterilized cotton swab, and a sterilized disc (Whatman AA disc, φ 6.0 mm) was placed. 10 μl of the test sample (sample concentration, 100 μg / disk) was absorbed into this disk, and after culturing at 37 ° C. for 4 days, the presence or absence of inhibition band formation was confirmed. Amoxicillin was used as a positive subject.
Table 1 shows the test results of sandalwood extract (see Example 1 below).

白檀のメタノール抽出物は供試したピロリ株に対して大きな阻止円を形成し、強い抗ピロリ活性があること、及び酢酸エチル層、n-ブタノール層、水層の各分配層での結果から、活性の主要な部分が酢酸エチル層に分配される成分によるものであることが示された。

Sandalwood methanol extract forms a large inhibition circle against the H. pylori strains tested, and has strong anti-H. Pylori activity, and from the results in each of the ethyl acetate layer, n-butanol layer, and water layer, It was shown that the major part of the activity was due to the components distributed in the ethyl acetate layer.

Next, Table 2 shows the test results of the sandalwood extract fraction (see Example 2 below).

Anti-pylori activity was also observed in components isolated from the ethyl acetate layer distribution of sandalwood methanol extract. As shown in the Examples, BKD0501 is (Z) -α-Santalol, BKD0503 is (Z) -β-Santalol, BKD0601 is (Z) -Lanceol, BKD1602 is α-Santaldiol, and BKD1613 is β-Santaldiol. , BKD1211 and BKD1205 are (Z) -camphylene-2α, 13-diol and (Z) -camphylene-2β, 13-diol, BKD1101 is (Z) -2α-hydroxyalbumol, and BKD1106 is (Z) -2β. -Hydroxy-14-hydro-β-santaol, BKD1303 and BKD1401 are respectively (Z) -3,4,5,6-tetradehydro-7-hydroxylanceol and (Z) -1β-hydroxy-2-hydro Lanceol.

Next, the effect on CAM-resistant H. pylori, which has been a problem in recent years, was tested.
Test example 2
Regarding (Z) -α-santalol, (Z) -β-santalol, and (Z) -lanceol, the minimum inhibitory concentration (MIC) was determined according to the agar plate dilution method defined by the Japanese Society of Chemotherapy. As a medium for measurement, a test substance diluted twice in a Mueller Hinton agar medium containing 5% by volume sheep defibrinated blood (final concentration, 1,000 to 0.1 μg / mL) was used. As test bacteria, H. pylori standard strain ATCC43504, clinical isolates SS-1, Sa-1, Sa-2, Sa-3, TPH30, and CAM resistant strains TS281 and TS648 were used. Helicobacter pylori is an ISO SENSI TEST agar plate containing 10% horse defibrinated blood, cultured in a microaerobic environment at 37 ° C for 4 days, collected colonies, and collected at a final concentration of 1 x 10 ⁷ Diluted with sterile physiological saline to ˜1 × 10 ⁸ CFU (colony forming unit) / mL. After inoculating this bacterial solution into a measuring medium using a microplanter (Sakuma Seisakusho) and culturing at 37 ° C for 4 days in a microaerobic environment, the minimum concentration at which growth was completely inhibited was taken as the MIC value. . The results are shown in Table 3.

  As indicated above, the MIC values for (Z) -α-santalol, (Z) -β-santalol, and (Z) -lanceol are 7.8-31.3 μg / mL, 7.8-31.3 μg / mL, respectively. mL, and 31.3 to 125 μg / mL. In particular, (Z) -α-santalol and (Z) -β-santalol showed strong antibacterial activity against CAM-resistant strains, whose increase has been a problem in recent years, like other test strains. . Moreover, it was recognized that the activity is comparable to CAM or more effective than CAM.

The present invention is a pharmaceutical composition for the treatment of H. pylori infection, comprising an sandalwood extract or an ingredient contained in the extract as an active ingredient.
Here, sandalwood extract refers to sandalwood extracted with a suitable organic solvent or water. Sandalwood used here is a dried heartwood of sandalwood (Santalum alubum L.). As a suitable organic solvent, for example, methanol and ethanol can be used, and a mixed solution with water may be used. Further, the sandalwood methanol extract is distributed into three layers of ethyl acetate, butanol and water (see Example 1 below), and the ethyl acetate layer distribution can be used as sandalwood extract. Further, the fraction may be fractionated using various columns, and the obtained anti-H. Pylori active fractions (for example, active fractions I to X, see Examples below) may be used.

  The present inventors include (Z) -α-Santalol, (Z) -β-Santalol, (Z) -Lanceol, α-Santaldiol, β-Santaldiol, (Z) in the active fraction. -Camphlen-2α, 13-diol and (Z) -camphlen-2β, 13-diol, (Z) -2α-hydroxyalbumol, (Z) -2β-hydroxy-14-hydro-β-santaol, (Z It was clarified that) -3,4,5,6-tetradehydro-7-hydroxylanceol and (Z) -1β-hydroxy-2-hydrolanceol were included. Pharmaceutical compositions for the treatment of H. pylori infections comprising each of these compounds or a mixture thereof as an active ingredient are also included in the present invention.

Each of these compounds whose chemical structure has been clarified can be extracted from sandalwood, extracted from plants other than sandalwood, or chemically synthesized (including semi-synthetic). These compounds can be used in the present invention including solvates thereof (including hydrates) and prodrugs.
The pharmaceutical composition of the present invention can be administered orally or parenterally to mammals such as humans (eg, humans, dogs, cats, monkeys, rats, mice, horses, cows, etc.) Oral administration is desirable. Examples of dosage forms for oral administration include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (hard gelatin capsules and soft gelatin capsules), syrups, and emulsions. And suspension agents. Examples of dosage forms for parenteral administration include injections, infusions, drops, and suppositories.

  As a method for producing the pharmaceutical composition of the present invention into the above dosage form, a known production method generally used in the art can be applied. In addition, it is usually prepared according to a conventional method, and if necessary, an excipient, a binder, a disintegrant, a lubricant, a sweetener, a surfactant, ordinarily used in the pharmaceutical field when producing the dosage form. Appropriate amounts of suspending agents, emulsifiers and the like can be contained as appropriate. It may also contain pharmaceutically inactive substances that are generally used in non-toxic and pharmaceutical formulations. For example, when the pharmaceutical composition of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and is produced into pills and granules. Can be produced by containing an excipient, a binder, a disintegrant and the like. In addition, when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions and suspensions, suspending agents, It can be produced by containing a surfactant, an emulsifier and the like.

  Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like. Examples of the binder include 5-10 wt% starch solution, 10-20 wt% gum arabic solution or gelatin solution, 1-5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin and the like. Examples of the disintegrant include starch and calcium carbonate. Examples of the lubricant include silica, purified talc, magnesium stearate, stearic acid, calcium stearate, polyethylene glycol and the like. Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like. Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like. Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like. Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.

When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. are added to the active ingredient as necessary, and an injection for subcutaneous, intramuscular or intravenous use is prepared by a conventional method.
Examples of pH adjusting agents and buffering agents include citric acid, acetic acid, phosphoric acid sodium salt, and the like. Examples of the stabilizer include L-cysteine, L-methionine, L-histidine and the like. Examples of solubilizing agents include ethanol, propylene glycol, arginine hydrochloride and the like, and it is also possible to add isotonic agents, preservatives, soothing agents and the like.

The pharmaceutical composition of the present invention is stable and has low toxicity and can be used safely. The daily dose varies depending on the patient's severity, age, weight, route of administration, etc., but when administered orally to patients with diseases such as gastric ulcers caused by Helicobacter pylori infection, 60 kg) The daily dose is in the range of 1 mg to 5 g, preferably about 3 mg to 1 g, in terms of the active ingredient sesquiterpene alcohol compound. This is administered 1 to several times per day. Toxicity is not observed within the above dose range. When administered parenterally, the daily dose for adults (body weight 60 kg) is in the range of 1 mg to 5 g, preferably about 3 mg to 1 g, in terms of the sesquiterpene alcohol compound as the active ingredient. This is administered 1 to several times per day.
Hereinafter, the present invention will be specifically described with reference to examples showing the extraction method of the sesquiterpene alcohol compound contained in the pharmaceutical composition of the present invention, test examples showing the antibacterial activity, and formulation examples thereof. However, the present invention is not limited by the description of these examples.

  2.8 kg of crushed sandalwood was digested and extracted with methanol (20 L) for 2 hours, and after natural filtration when warm, the filtrate was concentrated under reduced pressure. This operation was performed 3 times, and the concentrated methanol extract was partitioned with ethyl acetate, butanol and water. The residue obtained by concentrating each partition layer under reduced pressure was used as an ethyl acetate layer partition, a butanol layer partition, and an aqueous layer partition, respectively.

  The ethyl acetate layer of Example 1 was concentrated under reduced pressure at 50 ° C. to obtain a brown oily substance (178.0 g). The ethyl acetate layer was layered on a glass column packed with silica gel, fractionated with n-hexane-ethyl acetate (8: 2-0: 10) and ethyl acetate-methanol (8: 2-0: 10), antibacterial Fractions I and II having activity were obtained.

Isolation of (Z) -α-Santalol, (Z) -β-Santalol, and (Z) -Lanceol 300 mg out of 50.5 g of the active fraction I of Example 2 with GPC (chloroform) Fractionation was performed to obtain fractions III and IV. III and IV were further purified by SiO ₂ HPLC with n-hexane: ethyl acetate (4: 1) to obtain III to BKD0501 and BKD0503 and IV to BKD0601 as colorless oils (yield: 60.0 mg, 38.0). mg, and 8.0 mg). These substances were identified as (Z) -α-santalol, (Z) -β-santalol, and (Z) -lanceol, respectively. The results of EI-MS, ¹ H-NMR, and ¹³ C-NMR of the obtained compound are shown below.

(Z) -α-Santaroll
EI−MS: m / z 220 [M] ^+
1 H-NMR (400MHz, CDCl ₃ ) δ: 5.32 (1H, t, H-10), 4.15 (2H, s, H-13), 1.80 (3H, s, H-12), 1.00 (3H, s , H-15), 0.83 (3H, s, H-14) J (Hz): 9,10 = 7.2.
¹³ C-NMR (100MHz, CDCl ₃ ) δ: 10.6 (C-15), 17.5 (C-14), 19.5 (C-6), 19.5 (C-2), 21.2 (C-12), 22.9 (C -9), 27.4 (C-1), 31.0 (C-5), 31.5 (C-3), 35.0 (C-8), 38.2 (C-4), 45.9 (C-7), 61.6 (C- 13), 129.5 (C-10), 133.7 (C-11).

(Z) -β-Santalol
EI−MS: m / z 220 [M] ^+
1 H-NMR (400MHz, CDCl ₃ ) δ: 5.30 (1H, t, H-10), 4.75 (1H, s, H-14), 4.47 (1H, s, H-14), 4.15 (2H, s , H-13), 2.68 (1H, brs, H-1), 2.11 (1H, brs, H-4), 1.80 (3H, s, H-12), 1.05 (3H, s, H-15) J (Hz): 9,10 = 7.6.
¹³ C-NMR (100MHz, CDCl ₃ ) δ: 21.2 (C-12), 22.6 (C-15), 23.2 (C-9), 23.7 (C-5), 29.7 (C-6), 37.1 (C -7), 41.5 (C-8), 44.7 (C-4), 44.8 (C-3), 46.8 (C-1), 61.6 (C-13), 99.7 (C-14), 129.0 (C- 10), 133.9 (C-11), 166.2 (C-2).

(Z) -Lanceol
EI-MS: m / z 202 [M−H ₂ O] ^+
1 H-NMR (400MHz, CDCl ₃ ) δ: 5.42 (1H, brs, H-2), 5.33 (1H, t, H-10), 4.80 (1H, s, H-15), 4.75 (1H, s , H-15), 4.16 (2H, s, H-13), 1.82 (3H, s, H-12), 1.67 (3H, s, H-14) J (Hz): 9,10 = 7.2.
¹³ C-NMR (100MHz, CDCl ₃ ) δ: 21.3 (C-12), 23.4 (C-14), 26.4 (C-9), 28.3 (C-5), 30.7 (C-6) 31.4 (C- 3), 35.0 (C-8), 39.8 (C-4), 61.6 (C-13), 107.5 (C-15), 120.7 (C-2) 128.1 (C-10), 133.8 (C-1) , 134.5 (C-11), 153.9 (C-7).

The active fraction II (25.0 g) obtained in Example 2 was layered on a glass column packed with silica gel and fractionated with chloroform: methanol (10: 0 to 9: 1) to obtain a fraction having antibacterial activity. Next, it is layered on a glass column packed with TOYOPEARL HW-40, fractionated with chloroform: methanol (2: 1), further layered on a glass column packed with silica gel, and n-hexane: ethyl acetate (3: 1- Fractionation was performed in 0: 1) to obtain fractions V, VI, and VII.

Isolation of (Z) -2α-hydroxyalbumol and (Z) -2β-hydroxy-14-hydro-β-santaol
Fraction V353 mg was fractionated with n-hexane: ethyl acetate (2: 1) using SiO ₂ HPLC to obtain BKD1101 and BKD1106 (yield: 61.0 mg and 8.0 mg). These materials were identified as (Z) -2α-hydroxyalbumol and (Z) -2β-hydroxy-14-hydro-β-santaol, respectively. The results of EI-MS, ¹ H-NMR, and ¹³ C-NMR of the obtained compound are shown below.

(Z) -2α-Hydroxyalbumol
[α] _D = −2.3 ° (c 1.9, CHCl ₃ )
IR (KBr): 3375cm ^-1 (hydroxyl group)
HR FABMS m / z 261.1852 [M + Na] ⁺ (calcd for C ₁₅ H ₂₆ O ₂ Na, 261.1830)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.30 (1H, t, H-10), 4.16 (1H, d, H-13), 4.09 (1H, d, H-13), 3.30 (1H, s , H-2β), 2.07 (1H, m, H-9), 1.80 (3H, s, H-12), 1.76 (1H, m, H-4), 1.66 (1H, m, H-5α), 1.42 (1H, m, H-7), 1.09 (3H, s, H-14), 0.71 (3H, s, H-15) J (Hz): 9, 10 = 7.4, 13, 13 = 11.6.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 16.7 (C-15), 19.5 (C-14), 21.4 (C-12), 22.6 (C-9), 25.5 (C-6), 26.2 (C -5), 40.9 (C-7), 42.2 (C-3), 42.7 (C-8), 46.6 (C-4), 48.9 (C-1), 61.4 (C-13), 83.4 (C- 2), 129.3 (C-10), 133.9 (C-11).

(Z) -2β-Hydroxy-14-hydro-β-santaol
[α] _D = + 8.5 ° (c 0.9, CHCl ₃ )
IR (KBr): 3398cm ^-1 (hydroxyl group)
HR FABMS m / z 261.1821 [M + Na] ⁺ (calcd for C ₁₅ H ₂₆ O ₂ Na, 261.1830)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.35 (1H, brs, H-10), 4.21 (1H, d, J = 11.6, H-13), 4.00 (1H, d, J = 11.6, H- 13), 2.14 (1H, m, H-9), 1.80 (3H, s, H-12), 1.57 (1H, m, H-5α), 1.21 (3H, s, H-14), 0.89 (3H , s, H-15) J (Hz): 13, 13 = 11.6.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 19.9 (C-15), 21.8 (C-12), 22.3 (C-14), 23.2 (C-6), 24.0 (C-5), 24.7 (C -9), 34.2 (C-7), 38.1 (C-8), 46.2 (C-3), 47.6 (C-4), 52.2 (C-1), 61.7 (C-13), 81.3 (C- 2), 129.5 (C-10), 134.0 (C-11).

Isolation of (Z) -camphylene-2α, 13-diol and (Z) -camphylene-2β, 13-diol
Using SiO ₂ HPLC, the active fraction VI704 mg obtained in Example 4 was fractionated with n-hexane: ethyl acetate (1: 1), and BKD1205 (12 mg), BKD1211 (yield: 12.0 mg, and 65 mg) Fractions VIII and IX were obtained. These substances were identified as (Z) -camphylene-2α, 13-diol and (Z) -camphylene-2β, 13-diol, respectively. The results of EI-MS, ¹ H-NMR, and ¹³ C-NMR of the obtained compound are shown below.

(Z) -camphylene 2α, 13-diol
EI−MS: m / z 238 [M] ⁺
[α] _D = −11.5 ° (4.0, CHCl ₃ )
¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.32 (1H, t, H-10), 4.15 (2H, s, H-13), 4.08 (1H, d, H-2), 1.80 (3H, s , H-12), 0.80 (3H, s, H-14), 0.69 (3H, s, H-15) J (Hz): 10, 11 = 7.2.
¹³ C-NMR (100MHz, CDCl ₃ ) δ: 13.4 (C-15), 16.6 (C-14), 21.3 (C-12), 23.8 (C-9), 26.1 (C-6), 28.0 (C -5), 32.8 (C-8), 38.8 (C-3), 42.0 (C-4), 50.4 (C-1), 51.3 (C-7), 61.5 (C-13), 77.4 (C- 2), 129.1 (C-10), 134.0 (C-11).

(Z) -camphylene-2β, 13-diol
[α] _D = + 1.1 ° (c 1.4, CHCl ₃ )
IR (KBr) 3323cm ^-1 (Hydroxyl group)
HR EIMS m / z 238.1919 [M] ⁺ (calcd for C ₁₅ H ₂₆ O ₂ , 238.1933)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.35 (1H, t, H-12), 4.15 (1H, d, H-13), 4.09 (1H, d, H-13), 3.65 (1H, dd , H-2α), 1.58 (3H, s, H-12), 1.02 (1H, m, H-5α), 0.92 (1H, m, H-6α), 0.82 (3H, s, H-15), 0.66 (3H, s, H-14) J (Hz): 9, 10 = 7.4, 13, 13 = 11.8.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 11.4 (C-15), 16.8 (C-14), 21.4 (C-12), 23.3 (C-9), 27.1 (C-5), 33.6 (C -8), 34.4 (C-6), 39.9 (C-3), 41.9 (C-4), 49.3 (C-1), 50.0 (C-7), 61.3 (C-13), 79.7 (C- 2), 129.4 (C-10), 133.9 (C-11).

Isolation of α- santaldiol The active fraction VII634 mg obtained in Example 4 was fractionated with n-hexane: ethyl acetate (1: 2) using SiO ₂ HPLC to obtain BKD1602 (yield: 75 mg). And fraction X was obtained. This material was identified as α-santaldiol. The results of EI-MS, ¹ H-NMR, and ¹³ C-NMR of the obtained compound are shown below.

α-Santaldiol
EI-MS: m / z 218 [M−H ₂ O] ^+
1 H-NMR (400MHz, CDCl ₃ ) δ: 5.55 (1H, t, H-10), 4.30 (2H, s, H-13), 4.17 (2H, s, H-12), 0.99 (3H, s , H-15), 0.83 (3H, s, H-14) J (Hz): 9, 10 = 7.0.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 10.6 (C-15), 17.5 (C-14), 19.4 (C-6), 19.5 (C-2), 22.8 (C-9), 27.4 (C -1), 31.0 (C-5), 31.5 (C-3), 34.5 (C-8), 38.1 (C-4), 45.9 (C-7), 59.7 (C-13), 67.4 (C- 12), 132.1 (C-10), 136.4 (C-11).

Isolation of (Z) -3,4,5,6-tetradehydro-7-hydroxylanceol, (Z) -1β-hydroxy-2-hydrolanceol, and β-santaldiol Example 6 The active fractions VIII and IX obtained in 1 above and the active fraction X obtained in Example 7 were fractionated with GPC (methanol), respectively, and VIII to BKD1303, IX to BKD1401, X to BKD1613 (yield: 3 mg, 4 mg And 10 mg). These substances have been identified as (Z) -3,4,5,6-tetradehydro-7-hydroxylanceol, (Z) -1β-hydroxy-2-hydrolanceol, and β-santaldiol, respectively. . The results of EI-MS, ¹ H-NMR, and ¹³ C-NMR of the obtained compound are shown below.

(Z) -3,4,5,6-Tetradedehydro-7-hydroxylanceol
[α] _D = −5.0 ° (c 0.4, CHCl ₃ )
IR (KBr) 3375cm ^-1 (Hydroxyl group)
HR EIMS m / z 234.1648 [M] ⁺ (calcd for C ₁₅ H ₂₂ O ₂ , 234.1620)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.32 (2H, d, H-3, 5), 7.17 (2H, d, H-2, 6), 5.28 (1H, t, H-10), 4.01 (2H, s, H-13), 2.36 (3H, s, H-14), 2.07 (1H, m, H-9), 1.76 (3H, s, H-12), 1.55 (3H, s, H -15) J (Hz): 9, 10 = 7.0, 2, 3 = 8.0, 5, 6 = 8.0.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 21.0 (C-14), 21.4 (C-12), 22.6 (C-9), 30.8 (C-15), 43.8 (C-8), 61.5 (C -13), 74.9 (C-7), 124.7 (C-3), 124.7 (C-5), 128.4 (C-10), 128.9 (C-2), 128.9 (C-6), 134.6 (C- 11), 136.2 (C-1), 144.7 (C-4).

(Z) -1β-hydroxy-2-hydrolanceol
[α] _D = −3.0 ° (c 0.5, CHCl ₃ )
IR (KBr) 3373cm ^-1 (Hydroxyl group)
HR EIMS m / z 220.1826 [M−H ₂ O] ⁺ (calcd for C ₁₅ H ₂₄ O, 220.1827).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.33 (1H, t, H-10), 4.82 (1H, s, H-15), 4.72 (1H, s, H-15), 4.14 (2H, s , H-13), 1.82 (1H, m, H-4α), 1.81 (3H, s, H-12), 1.56 (1H, m, H-5α), 1.45 (1H, m, H-6α), 1.25 (3H, s, H-14) J (Hz): 9, 10 = 6.8.
¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 21.3 (C-12), 26.4 (C-9), 27.4 (C-3), 27.4 (C-5), 31.4 (C-14), 34.9 (C -8), 38.9 (C-2), 38.9 (C-6), 43.6 (C-4), 61.6 (C-13), 69.0 (C-1), 107.6 (C-15), 128.1 (C- 10), 134.5 (C-11), 153.9 (C-7).

β-Santaldiol
[α] _D = −2.3 ° (c 1.9, CHCl ₃ )
IR (KBr): 3367cm ^-1 (hydroxyl group)
HR FABMS: 261.1852 (C ₁₅ H ₂₆ O ₂ Na, calcd. For 261.1830)
¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.30 (1H, t, H-10), 4.16 (1H, d, H-13), 4.09 (1H, d, H-13), 3.30 (1H, s , H-2), 1.80 (3H, s, H-12), 1.20 (3H, s, H-14), 0.74 (3H, s, H-15) J (Hz): 9, 10 = 7.4; 13 , 13 = 11.6.
¹³ C-NMR (100MHz, CDCl ₃ ) δ: 16.7 (C-15), 19.5 (C-14), 21.4 (C-12), 22.6 (C-9), 25.5 (C-6), 26.2 (C -5), 40.9 (C-7), 42.2 (C-3), 42.7 (C-8), 46.6 (C-4), 48.9 (C-1), 61.4 (C-13), 83.4 (C- 2), 129.3 (C-10), 133.9 (C-11).

Formulation Example 1 Tablet One tablet (250 mg) contains 75 mg of sandalwood extract or 25 mg of one kind of sesquiterpene alcohol contained in sandalwood. As additives, lactose 98 mg or 148 mg, corn starch 50 mg, magnesium stearate 2 mg, and cellulose 25 mg are prepared, and tablets are prepared according to a conventional method.

Formulation Example 2 Hard gelatin capsule One capsule (340 mg) of hard gelatin capsule contains 100 mg of sandalwood extract or 30 mg of one kind of sesquiterpene alcohol contained in sandalwood. As an additive, 115 mg or 185 mg of lactose, 70 mg of corn starch, 5 mg of magnesium stearate, and 50 mg of cellulose are prepared, and capsules are prepared according to a conventional method.

Formulation Example 3 Granules 1 g of granules contains 300 mg of sandalwood extract or 100 mg of sesquiterpene alcohol contained in sandalwood. As additives, 320 mg or 520 mg of lactose, 300 mg of corn starch, and 80 mg of cellulose are prepared, and granules are prepared according to a conventional method.

The above-mentioned compound contained in sandalwood extract and / or sandalwood has an antibacterial action in vivo, particularly a strong antibacterial activity against Helicobacter spp. Represented by H. pylori. It is effective in preventing or treating “duodenal ulcer, gastric ulcer, gastritis (including chronic gastritis), gastric cancer, etc.”, which are diseases caused by the above.

Claims (3)

A pharmaceutical composition for treating H. pylori infection, comprising a sandalwood-containing component as an active ingredient. The pharmaceutical composition of claim 1, wherein the sandalwood-containing component is an extract from sandalwood (Santali Lignum). Sandalwood-containing component is (Z) -α-santalol, (Z) -β-santalol, (Z) -lanceol, α-santaldiol, β-santaldiol, (Z) -camphlen-2α, 13-diol, (Z) -camphylene-2β, 13-diol, (Z) -2α-hydroxyalbumol, (Z) -2β-hydroxy-14-hydro-β-santaol, (Z) -3,4,5,6 The pharmaceutical composition according to claim 1, which is a sesquiterpene alcohol or a mixture thereof selected from the group consisting of -tetradehydro-7-hydroxylanceol and (Z) -1β-hydroxy-2-hydrolanceol.